The purpose of this project is to elucidate the principles of treatment of chronic pain syndromes that are considered resistant to conventional treatment, such as pain caused by peripheral neuropathy and nerve injury, and by advanced cancer. Fifty-eight patients with post-herpetic neuralgia were treated with 6 weeks of amitriptyline, lorazepam, and/or placebo in a double-blind crossover study. Amitriptyline provided substantial relief in 1/3 of patients, and slight relief in another 1/3, while lorazepam and placebo did not relieve pain. The observation that only 1/4 of the patients were considered depressed by psychiatric interview, and little change in mood occurred during treatment suggests a specific pain-relieving effect for amitriptyline--i.e., analgesia was not mediated through the drug's antidepressant effect. In contrast to prevailing clinical anecdote, low doses of amitriptyline were less effective than higher doses through 150 mg/day; blood levels were also related to analgesia. Sedation and anti-cholinergic effects limited dosage, however, pointing the need for more specific and less toxic pain-relieving agents. Desipramine, a related tricyclic with fewer side-effects and a relatively specific action to promote central norepinephrine action, has been given to 20 patients thus far in a similar crossover placebo-controlled 6-week treatment. We have not yet broken the code, but dosages are 2-3 times as high as in the amitriptyline study, and more than half of patients are reporting substantial relief with one of the treatments. A survey of 50 NIH patients with AIDS or related disorders showed that about 1/3 of the patients have pain related to AIDS, and another 1/3 have unrelated pain. Pain from HIV-related neuropathy is common in patients with advanced disease, who would benefit from more specific, nontoxic treatments, as discussed above; few of these patients are being seen yet at the Clinical Center. Four other studies were approved by the IRB and will shortly begin.